Proliferation of human Schwann cells induced by neu differentiation factor isoforms

Neu differentiation factor (NDF), a 44-kD polypeptide, is a member of the neuregulin family which also includes glial growth factor, heregulin and acetylcholine-receptor-inducing activity. Previous studies have demonstrated that NDF/glial growth factor/heregulin/acetylcholine-receptor-including activity are products of neurons and mediate proliferation, differentiation and gene expression in Schwann cells of experimental animals. In the present study, the efficacy of different isoforms of NDF in stimulating human Schwann cell proliferation is investigated in Schwann-cell-enriched cultures derived from fetal human dorsal root ganglia (15-20 weeks gestation). NDF isoforms examined include alpha1, alpha2, EGF-like domain alpha2 (EGFalpha2), alpha3, beta1, EGFbeta1, EGFbeta, beta2 and beta3. For the assessment of Schwann cell proliferation, double immunostaining using antibodies specific for S-100 protein and bromodeoxyuridine was used. While treatment of Schwann cells with NDF alpha isoforms (alpha1, alpha2, alpha3 and EGFalpha2) had little effect on Schwann cell proliferation, NDF beta isoforms (beta1, beta2, beta3, EGFbeta1 and EGFbeta) induced a greatly enhanced proliferation in Schwann cells. The proliferation index in unstimulated Schwann cells was 1.3 +/- 0.9%, whereas in Schwann cells treated with NDFbeta isoforms the proliferation index was 21.8 +/- 2.2%. The finding that the truncated beta isoforms such as EGFbeta1 and EGFbeta retain a mitogenic activity as potent as full-length beta isoform indicates that the C-terminal portion of the EGF-like domain is responsible for its receptor binding and subsequent biological activity.